IPAH is characterized by obstruction of the small pulmonary arteries by medial hypertrophy, concentric intimal fibrosis, fibrinoid degeneration, thrombotic lesions and plexiform changes. Uncertainty about the cell(s) of origin of IPAH and the pathogenetic sequence leading to concentric fibrosis and plexiform lesions has persisted for many years.
Some investigators propose that proliferation of vascular smooth muscle cells and their transformation into myofibroblasts are the major pathogenetic events leading to IPAH and plexiform lesion formation.
Others believe that endothelial cells responding to cytokines, growth factors, or vascular injury initiate the disease.
Lesions identical with those of IPAH can be found in the lungs of patients with pulmonary hypertension due to a variety of etiologies, including HIV infection, portal hypertension, congenital heart disease, collagen vascular diseases, and ingestions. It is unclear whether pulmonary vascular proliferation and remodeling or vasoconstriction have an initiating role in the pathogenesis of IPAH.
Studies of families affected by IPAH have led to the discovery of mutations in the gene encoding bone morphogenetic protein receptor 2 (BMPR2) as a major cause for familial IPAH. BMPR2 is a protein of the TGF ß receptor superfamily, which binds several cytokines. Along with a BMP type 1 receptor, BMPR2 binds ligand in a heterodimeric complex on the cell surface and propagates signal via SMAD molecules. By use of immunohistochemistry on explanted lung tissue, investigators have found that endothelial cell expression of BMPR2 is decreased in patients with IPAH compared with healthy controls.
Cultured pulmonary arterial smooth muscle cells from patients with IPAH show dysregulated growth inhibition when exposed to BMP proteins and TGF ß. Other investigators have described somatic mutations in BMPRI in the endothelial cells of plexiform lesions.
However, because phenotypic disease occurs in only about 20% of individuals with BMPR2 mutations, the existence of important modifier genes or environmental triggers seems certain. The study of polymorphisms in modifying genes is in its infancy. Multiple mediator pathways have been implicated in the pathogenesis of IPAH, including, but not limited to, serotonin and serotonin transporter, potassium channels, HIV and HHV8 infection, angiopoeitin, VEGF, tenascin, G protein coupled mediators, endothelin, estrogens and VIP. Each of these areas of potential importance in IPAH needs further investigation.
The elucidation of the molecular pathways that lead to IPAH have been handicapped by the lack of animal models that closely representative of the human disease. Studies could be performed on tissues from patients with active disease if the tissue were available. Unfortunately, open-lung biopsy is prohibitive with respect to its morbidity, and, thus is not a reasonable avenue to pursue to obtain tissue for studies.
Post-mortem tissues from IPAH patients who have died is problematic since the logistics preclude harvesting lungs from these patients in a timely manner that would allow the adequate tissue handling and preparation for the studies that are necessary.
Consequently, lungs explanted from patients with IPAH undergoing lung transplantation provide the only real opportunity to investigate the cellular and molecular pathways involved in IPAH.
